Abstract
Brain metastases are a significant complication of non-small-cell lung cancer (NSCLC), contributing to high morbidity and mortality rates. The introduction of immune checkpoint inhibitors (ICIs) has opened new therapeutic avenues for patients with NSCLC, including those with brain metastases. However, the distinct microenvironment of the brain presents unique challenges to the effectiveness of these treatments. This review examines the mechanisms by which ICIs impact brain metastases from NSCLC, with particular focus on immune cell trafficking across the blood-brain barrier (BBB), tumor microenvironment modulation, and transcriptomic evolution of brain-tropic tumor clones. Unlike prior reviews, we integrate emerging data from single-cell and spatial transcriptomic studies, BBB disruption mechanisms, and the tumor-supportive role of brain-resident glia. We also critically evaluate key clinical trials and real-world evidence, highlighting differences in ICI efficacy across patient subgroups and therapeutic contexts. Additionally, we address the evolving role of surgical resection, stereotactic radiosurgery, and cerebrospinal-fluid-based biomarkers in optimizing ICI-based treatment strategies. This synthesis provides a comprehensive, mechanistic, and clinically relevant framework for improving outcomes in patients with NSCLC brain metastases treated with immunotherapy.